Vertebral fractures are the most common type of osteoporotic fracture, afflicting one in three women and one in six men over the age of 50. Despite their high prevalence, sensitive and specific estimates of vertebral fracture risk have remained elusive. The limitations of current approaches to estimating vertebral strength and fracture risk, which rely heavily on measurement of the average bone mineral density (BMD), are widely recognized. However, alternative methods have been lacking with respect to validation and clear advantages over the average BMD approach. Our recent data address this critical gap in knowledge and translation by demonstrating the use of clinically feasible measurements made from quantitative computed tomography (QCT) scans to enhance predictions of vertebral failure. Using QCT-derived measures of the distribution of bone tissue throughout the vertebra, we have found that the magnitude of the intra-vertebral heterogeneity in BMD provides improved predictions of vertebral strength and is lower in women with vs. without vertebral fracture. These data also indicate that multiple, characteristic spatial distributions (patterns) of BMD within the vertebra can confer high bone strength, and that the associations between these patterns and strength may be modulated by the severity of degeneration in the adjacent intervertebral discs (IVDs). We now propose to define relationships among intra-vertebral heterogeneity in BMD, vertebral failure, and IVD degeneration in population-based studies and complementary ex vivo studies. Aim #1 will use a case-control study design with previously acquired QCT scans in men and women enrolled with the Framingham Heart Study (FHS) Multidetector QCT study to test the hypothesis that decreased magnitude of heterogeneity is associated with increased risk of prevalent fracture. Aim #2 will use an age- and sex-stratified, random sample from the FHS QCT cohort to determine associations between the spatial distribution of BMD and IVD health, followed by ex vivo studies that define how these associations can influence vertebral strength. Our dual hypotheses in Aim #2 are that the spatial patterns of BMD are associated with IVD health and that vertebral strength depends on the congruence between the spatial BMD pattern and the load distribution supplied by the IVDs. Aim #3 will continue our clinically focused, biomechanical investigations via a novel experimental approach that provides much-needed evaluation of the accuracy of QCT-based finite element (FE) models of vertebral failure. This aim will test the hypothesis that the accuracy of the FE predictions is improved by incorporating clinically obtainable assessments of IVD health. Together, these Aims constitute a major step towards reducing the burden of vertebral fractures. This work partners study of the phenomenon of intra-vertebral heterogeneity in a community-dwelling population with case-control and laboratory studies of the biomechanical consequences of this heterogeneity. As such, the results will provide a widely applicable, integrated assessment of vertebral health, complete with translatable tools to set a new standard for estimation of fracture risk.